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Abstract

Perivascular epithelioid cell tumors (PEComas) encompass a group of rare mesenchymal
neoplasms, which typically have a perivascular location with dual melanocytic and
muscular differentiation. They are found in a variety of localizations, though lesions
in the liver are exceedingly rare. Because of their rarity, the clinical, radiological
and histological features of these tumors have yet to be established. This is why,
it seems appropriate to report the observation of this rare hepatic tumor with a literary
review including others published cases, assessing through it, clinicopathologic and
radiologic features of all reported cases as well as their follow-up whenever possible.

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Keywords:

PEComas; Liver neoplasms; Perivascular epithelioid cell

Background

Perivascular epithelioid cell neoplasms (PEComas) formed a rare group of related mesenchymal
tumors composed of histologically and immunohistochimically distinctive perivascular
cells (PECs), first proposed by Bonetti et al. in 1992. The members of this family include angiomyolipoma, lymphangioleiomyomatosis,
pulmonary clear cell “sugar” tumors and PEComa-NOS
[1]. This last entity, first introduced by Zamboni and al in 1996, to describe neoplasms
composed solely of PECs in his case report
[2]. Many anatomic sites can be affected, but the uterus is the more common. Cases that
arise from the liver are extremely rare
[1]. To the best of our knowledge, Only 20 hepatic PEComas, composed solely of PECs,
have been reported in the current literature, mostly, as single-case reports.

The following report presents an additional case of primary liver PEComa appearing
in a 63-years-old woman, followed by a short synopsis about previously published cases.
We discuss the clinicopathological features, the immunophenotype and the differential
diagnosis to improve awareness about this type of tumor and how to diagnose it.

Case presentation

A 63-year-old woman presented to gastroenterology department with a 1-year history
of atypical pain in the right upper abdominal quadrant, with significant fatigue and
weight loss.

Her past medical history was unremarkable. She had no evidence of cirrhosis, viral
hepatitis or tuberous sclerosis complex (Bourneville’s disease). Physical examination
revealed only mild hepatomegaly without palpable mass or jaundice. Laboratory examinations
showed normal liver function tests and tumoral marquers (AFP, CEA).Initial abdominal
ultrasonography revealed a solitary, heterogeneous and hypoechoic mass in the liver,
with an ill-demarcated margin. Color Doppler flow images showed abundant blood flow
in the marginal area of the tumour. Subsequent CT and abdominal MRI confirmed this
intrahepatic mass to be located in the fourth segment (IV), measuring 6,4 × 8 cm in
diameters (Figure
1: A, B, C, D and E). Neither lymphadenopathy nor portal vein involvement was present.
No additional lesion was detected. Given the hypervascular character, the lack of
adipose tissue and thick-walled blood vessels, the lesion has been interpreted as
hemangiomas, atypical hepatocellular carcinoma or metastatic lesion. Owing to the
deteriorating clinical situation and the ambiguous imaging findings, a central segmentectomy
of the liver with a cholecystectomy was performed.

Figure 1.Radiological features of the tumor. A) precontrasted CT scan revealed a low-density mass of segment IV of the liver with
ill-defined borders. B) Contrast CT showing inhomogeneous contrast enhancement of tumor in the portal phase.
C) A mass described above had a low signal on T1-Weighted MRI, it became hyperintense
on T2-Weighted images (D), and presented a strong and heterogeneous enhancement after injection of gadolinium
(E).

Gross examination revealed a 6 × 8 cm, solitary lesion with an ill-demarcated margin.
The external surface of the mass was smooth, white-tan in color. Cut sections through
the mass showed solid and tiny cystic areas with multiples congested blood vessels.
The hepatic tissues around the mass were normal. The authors took 15 sections from
different parts of the tumor and 2 sections from the adjacent liver.Routine hematoxylin-eosin-stained
sections from formalin-fixed, paraffin-embedded tissue ware examined. Histologically,
the tumor was composed of nests and sheets of larges and round to polygonal cells,
separated by a rich sinusoidal vascular network. The cells showed abundant cytoplasm
that varied from eosinophilic granular to clear, with distinct cell border. The nuclei
were round to oval with finely distributed to vesicular chromatin and small nucleoli.
Focal nuclear pleomorphism was observed, without necrosis, mitotic figures or angiolymphatic
invasion [Figure
2]. The tumor frequently showed dilated vascular channels with radial arrangement of
tumor cells. In numerous sections, adipocytes, thick-walled vessels and hematopoietic
cells were entirely absent. The adjacent liver was microscopically normal.Immunohistochemical
study showed a strong and diffuse expression of HMB45 and smooth muscle actin (SMA),
while Melan-A was focally positive. The neoplastic cells were negative for S100 protein
and Pancytokeratin [Figure
3].

On the basis of the morphologic characteristics and immunohistochemical results, a
diagnosis of hepatic PEComa was made, with infiltration of the margins.

The patient recovered uneventfully and was discharged 2 weeks after surgery, without
any adjuvant treatment. At present, 9 months after the surgery, she is under regular
clinical follow-up with no evidence of primary recurrence or metastasis.

Bibliographic research

For the literature review, a systematic search for PEComa related reports published
was performed using PubMed
[3] with de keywords: PEComa, perivascular epithelioid cell, angiomyolipoma, liver and
HMB45.

Discussion

We have described a hepatic PEComa composed purely of epithelioid cells with lack
of lipocytes and abnormal vessels. In our case, no other component element of the
tumour could be found anywhere even though extensive examination of most of the tumour
tissue was performed.

The descriptive term “perivascular epithelioid cells (PECs)” were first proposed by
Bonetti et al. in 1992 to describe an “unusual atypical cell type” which typically has a perivascular
distribution, with dual melanocytic and myoid differentiation
[4]. Despite the lack of evidence of a normal anatomical homologue, in 2002, the World
Health Organization has given formal recognition to the concept of this novel cell
type and of PEC-derived tumors. “PEComa family” includes now many distinct clinicopathologic
entities such as angiomyolipoma (AML), lymphangiomyomatosis and clear cell “sugar”
tumors of the lung,
[1]. Some of them have been linked to tuberous sclerosis complex, especially AML of the
kidney. The group comprising solely PECs is rare; it has been discriminated from classic
angiomyolipoma by various appellations including monotypic epithelioid AML, clear
cell myomelanocytic tumor, primary extrapulmonary sugar tumor, and PEComas-NOS or
simple PEComa
[5,6]. The first reported case in the liver was in 2000, when Yamasaki S described this
entity diagnosed incidentally in a 30-years-old women
[7]. Since, twenty prior case reports were found in a MEDLINE search and we auditioned
our case to this data, the main findings for these cases are summarized in Additional
file
1: Table S1
[6-24].

Hepatic PEComa was commonly diagnosed following abdominal pain or mass, occasionally
with incidental finding. One case had synchronous GIST. No one had history or symptoms
of TSC. The routine laboratory investigations were noncontributory.

There was a marked female predominance (17 women and 4 men), and the mean age at diagnosis
was 46.3 years (range 25–60 years). All tumors were presented as a solitary lesion,
most often in the right lobe, which poses a clinical and radiological diagnostic challenge.
They varied from 0.8-17 cm in greatest dimension (mean 8.1 cm).

PEComas exhibit a wide spectrum of imaging findings. Hepatic PEComas can be of any
echogenecity, most often, with abundant blood flow in or surrounding the lesion. As
our case, on CT scan, most neoplasms present as hypo intense with significant enhancement
on arterial phase. The portal phase was variable. Almost all lesions reported show
low-signal on T1-weighted images, high-signal on T2-weighted images. These radiologic
findings of hypervascular lesion can be confused, most often, with those of hepatocellular
carcinoma or simple haemangioma
[25].

The diagnostic was most often confirmed by pathology finding. PEComa cells are characterized
by their perivascular location, often with radial arrangement around the vascular
lumen. Typically, tumor cells are epithelioid and spindle-shaped resembling smooth
muscle cells, and tend to have abundant clear to eosinophilic pale granular cytoplasm
[5]. Few cases are reported with prominent nucleoli and mild nuclear pleomorphism as
seen in our case. The presence of melanin pigment is extremely rare, reported only
in 3 cases
[13,19,20].

The most important finding is positive immunostaining with both melanocytic (HMB45
and/or melan A) and smooth muscle (actin and/or desmin) markers
[5]. In all reports, there was a diffuse positivity for HMB45. Melan A and SMA were frequently
positive. S100 protein, desmin and vimentine were more often negative.

Monotypic epithelioid angiomyolipoma should be differentiated from epithelioid smooth
muscle tumour. Immunohistochemically or ultrastructurally, both tumours express markers
of smooth muscle differentiation, but only monotypic epithelioid angiomyolipoma expresses
markers of melanogenesis. Other common differential diagnoses include hepatic adenoma
and carcinoma, gastrointestinal stromal tumors, epithelioid sarcoma, paraganglioma,
and metastatic sarcomatoid renal cell carcinoma as well as oncocytic and clear cell
carcinoma. The positivity for melanocytic markers and the negativity for multiples
markers including CK, CD117, chromogranin and synaptophysin confirmed the diagnosis
[5,15] (Table
1).

Table 1.Immunohistochemistry in the differential diagnosis of PEComa tumors

The possibility of metastatic malignant melanoma should always be removed. In the
present case, the patient had no history or clinical manifestation of cutaneous or
mucosal melanoma. All the more, we had a negative immunostaining with S100 protein.
This last protein was expressed in many reported cases
[7,15,19-21], thereby making the differential diagnosis more difficult.

Although the vast majority of reported PEComa showed a benign course; some are aggressive
with locally destructive recurrences, and distant metastasis. To date, defined criteria
for malignancy in hepatic PEComa have not been established. Folpe et al.
[26] proposed a classification of PEComas into benign, uncertain malignant potential,
and malignant based on the presence of seven worrisome histological features: Tumor
size > 5 cm, infiltrative growth pattern, high nuclear grade, high cellularity, necrosis,
mitotic activity > 1/50 HFP and vascular invasion. Thereby, PEComa with two or more
worrisome histologic features should be considered as malignant. Tumors with nuclear
neoplasm only or size more than 5 cm only were considered as a neoplasm of uncertain
malignant potential. Only one case of malignant PEComa was reported in the liver
[9], in which the diagnosis was established based on the presence of metastasis. The
microscopic findings, in this case, were consistent with a benign status except for
size more than 5 cm. Seven were thought to have malignant potential according to Folpe’s
criteria, but did not exhibit recurrence or metastasis. This might be attributable
to the fact that the follow-up durations in these cases were relatively short (3 to
24 month). In our case the patient exhibited two features that favored malignancy,
tumor size and infiltrative growth pattern, requiring therefore, a close and long-term
follow-up.

There is no specific treatment protocol for hepatic PEComa; the most of neoplasm were
surgically treated without any adjuvant therapy.

Conclusion

Primary PEComas of the liver are still a curiosity and therefore the diagnostic approach,
treatment modalities and the follow-up are challenging. Their prognosis remains unpredictable;
it should be regarded as tumors with uncertain biological potential that require strict
and long-term follow-up.

Consent from the patient

Written informed consent was obtained from the patient for publication of this case
report and any accompanying images.